{"gene":"IL20RA","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2001,"finding":"IL-24 (MDA-7/MOB-5) signals through two heterodimeric receptors: IL-22R1/IL-20R2 and IL-20R1/IL-20R2 (where IL-20R1 = IL-20RA). COS cells transfected with either receptor heterodimer bind IL-24 with similar saturation kinetics, and IL-24 binding to these receptors activates STAT transcription factors in keratinocytes and baby hamster kidney cells.","method":"Ligand-receptor binding assay, STAT activation assay in COS cells and keratinocytes, transfection of ectopic receptors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding and signaling assays with multiple cell types, replicated in endogenous and ectopic systems","pmids":["11706020"],"is_preprint":false},{"year":2011,"finding":"The IL-20-IL-20R1(IL-20RA)-IL-20R2 ternary complex was crystallized, with crystals diffracting to 3 Å resolution, establishing that IL-20RA forms a ternary complex with IL-20 and IL-20R2.","method":"Protein purification, crystallization, X-ray diffraction","journal":"Acta crystallographica. Section F, Structural biology and crystallization communications","confidence":"Medium","confidence_rationale":"Tier 1 — crystal structure obtained but preliminary report without full structure determination or functional mutagenesis","pmids":["22232181"],"is_preprint":false},{"year":2014,"finding":"IL-20 signals through IL-20R1 (IL-20RA)-containing receptor complexes on hepatic stellate cells and hepatocytes to upregulate TGF-β1, TNF-α, and Col-I; anti-IL-20R1 monoclonal antibody (51D) and IL-20R1-deficient mice were protected from CCl4-induced liver fibrosis, placing IL-20RA upstream of TGF-β1 signaling in liver injury.","method":"Anti-IL-20R1 monoclonal antibody blockade, IL-20R1 knockout mice, CCl4-induced liver injury model, cell-based assays","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout plus antibody blockade with defined fibrosis phenotype, multiple orthogonal approaches","pmids":["24763901"],"is_preprint":false},{"year":2019,"finding":"Flexible regions of IL-24 govern its promiscuous binding to IL-20R1 (IL-20RA) and IL-22R1 (shared receptors 1); a single wild-type residue T198 on IL-24 is critical for binding affinity to IL-20R1 and IL-22R1, as its mutation abolishes binding while reintroduction restores ~80% binding affinity and signaling capacity.","method":"Protein engineering, binding affinity measurements, signaling assays, homology modeling, crystallography (IL-24B, PDB ID 6GG1)","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 — structure combined with site-specific mutagenesis and functional signaling assays","pmids":["31152679"],"is_preprint":false},{"year":2019,"finding":"In Crohn's disease intestinal lymphatic endothelial cells, mTOR signaling drives IL-20RA expression, and IL-20RA-mediated intracellular signaling controls leukocyte (LPMC) transmigration through the lymphatic endothelium, placing IL-20RA downstream of mTOR in regulating immune cell trafficking.","method":"Transcriptomic profiling of isolated human intestinal lymphatic endothelial cells, transwell co-culture transmigration assay with LPMCs","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional transmigration assay with transcriptomic pathway identification, single lab","pmids":["31426584"],"is_preprint":false},{"year":2021,"finding":"IL-20RA activates the JAK1-STAT3-SOX2 signaling axis in breast cancer cells, leading to increased expression of PD-L1 and reduced recruitment of CD8+ T cells and NK cells; IL-20RA also increases the proportion of myeloid-derived suppressor cells, promoting an immunosuppressive tumor microenvironment.","method":"Gain- and loss-of-function experiments, western blot, flow cytometry, in vivo mouse tumor models","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD/OE, flow cytometry, in vivo), single lab","pmids":["33456560"],"is_preprint":false},{"year":2021,"finding":"MiR-452 directly targets IL-20RA mRNA (validated by luciferase reporter assay); overexpression of MiR-452 or IL-20RA knockdown decreases expression of IL-20RA, JAK1, and STAT3 (but not STAT1), establishing that IL-20RA mediates JAK1-STAT3 signaling downstream of miR-452 regulation.","method":"Luciferase reporter assay, siRNA knockdown, western blot, RT-PCR","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 — direct target validation by luciferase assay combined with KD phenotype, single lab","pmids":["34283251"],"is_preprint":false},{"year":2021,"finding":"IL-19 signals through IL-20R1 (IL-20RA) to activate ERK and Nrf2, promoting CD163 expression and hematoma clearance after germinal matrix hemorrhage; IL-20R1 CRISPR knockdown abolished the beneficial effects of rIL-19 treatment.","method":"CRISPR knockdown of IL-20R1 in rat pup GMH model, western blot, immunohistochemistry, hemoglobin assay, neurobehavioral testing","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR loss-of-function with defined molecular pathway (IL-20R1/ERK/Nrf2) and functional readout","pmids":["33532035"],"is_preprint":false},{"year":2018,"finding":"The intergenic variant rs6927172 at 6q23 acts as a regulatory element that controls IL-20RA expression through chromatin looping; CRISPR/Cas9 deletion of this element altered IL-20RA (and TNFAIP3) expression, with EMSA showing the variant affects NF-κB transcription factor binding at this locus.","method":"CRISPR/Cas9 deletion, EMSA, western blot, chromatin conformation capture (3C), TALE-based transcriptional analysis","journal":"Genes and immunity","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (CRISPR KO, EMSA, 3C, TALE) establishing regulatory mechanism","pmids":["29483615"],"is_preprint":false},{"year":2025,"finding":"IL-20RA promotes epithelial-mesenchymal transition (EMT) through the STAT3/SNAIL pathway in Wilms tumor; IL-20RA knockdown decreased EMT markers, and IL-20RA was shown to act upstream of STAT3-SNAIL in driving tumor progression.","method":"siRNA knockdown, western blot, functional assays for EMT","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single KD approach with pathway inference","pmids":["40185911"],"is_preprint":false},{"year":2024,"finding":"In pig Sertoli cells, IL-20RA knockdown affected mitochondrial superoxide production and catalase secretion, indicating IL-20RA mediates antioxidant protection of mitochondria in these cells.","method":"siRNA knockdown, ROS measurement, mitochondrial function assays, transcriptomic analysis","journal":"Antioxidants (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 — single KD experiment in a non-mammalian model (pig), single lab","pmids":["39765872"],"is_preprint":false}],"current_model":"IL-20RA (IL-20R1) functions as the signaling subunit of heterodimeric cytokine receptor complexes (IL-20RA/IL-20R2 and IL-22R1/IL-20R2) that bind IL-20, IL-19, and IL-24; upon ligand binding, IL-20RA activates intracellular JAK1-STAT3 (and ERK/Nrf2) signaling cascades to regulate inflammation, tissue homeostasis, immune cell trafficking, and—when dysregulated—cancer stemness and immune evasion, with receptor expression itself controlled by an NF-κB-bound enhancer element at 6q23."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing that IL-20RA functions as a ligand-binding subunit in two heterodimeric receptor complexes for IL-24 resolved how a single cytokine engages distinct receptor pairs to activate STAT signaling.","evidence":"Ligand-receptor binding and STAT activation assays in COS cells, keratinocytes, and BHK cells transfected with IL-20R1/IL-20R2 or IL-22R1/IL-20R2","pmids":["11706020"],"confidence":"High","gaps":["Downstream STAT family member specificity not resolved","Binding affinities for IL-19 and IL-20 through these complexes not measured","No structural basis for receptor assembly"]},{"year":2011,"claim":"Crystallization of the IL-20–IL-20RA–IL-20R2 ternary complex provided the first structural evidence that IL-20RA directly contacts both ligand and co-receptor in a defined stoichiometric assembly.","evidence":"Protein purification and X-ray crystallography at 3 Å resolution","pmids":["22232181"],"confidence":"Medium","gaps":["Full atomic structure and interface residue analysis not yet reported","No mutagenesis validation of predicted contact sites","Structure of IL-19 or IL-24 ternary complexes not determined"]},{"year":2014,"claim":"Demonstrating that IL-20RA-deficient mice and anti-IL-20RA antibody blockade prevented liver fibrosis established IL-20RA as a required upstream activator of TGF-β1 and pro-fibrotic gene expression in hepatic stellate cells.","evidence":"IL-20R1 knockout mice and anti-IL-20R1 monoclonal antibody (51D) in CCl4-induced liver fibrosis model","pmids":["24763901"],"confidence":"High","gaps":["Precise signaling intermediates between IL-20RA and TGF-β1 induction not mapped","Whether IL-19 or IL-24 also drives fibrosis through this receptor not tested","Human disease relevance not validated"]},{"year":2018,"claim":"Identification of an NF-κB-bound intergenic enhancer at 6q23 that controls IL-20RA expression via chromatin looping revealed how genetic variation at this locus can tune receptor abundance.","evidence":"CRISPR/Cas9 enhancer deletion, EMSA, chromatin conformation capture (3C), and TALE-based transcriptional analysis","pmids":["29483615"],"confidence":"High","gaps":["Cell-type specificity of enhancer activity not fully characterized","Quantitative relationship between enhancer variant genotype and surface IL-20RA protein levels not established","Whether this enhancer co-regulates TNFAIP3 independently of IL-20RA not resolved"]},{"year":2019,"claim":"Structural and mutagenesis studies on IL-24 identified T198 as a critical residue governing promiscuous binding to IL-20RA and IL-22R1, explaining how flexible ligand regions enable receptor sharing.","evidence":"Protein engineering, binding affinity measurements, signaling assays, and crystal structure of IL-24B variant (PDB 6GG1)","pmids":["31152679"],"confidence":"High","gaps":["Reciprocal mutations on IL-20RA that affect binding not identified","Whether IL-19 uses analogous structural determinants unknown","No kinetic (SPR) data for mutant binding"]},{"year":2019,"claim":"Finding that mTOR signaling drives IL-20RA expression in Crohn's disease lymphatic endothelial cells and that IL-20RA mediates leukocyte transmigration placed the receptor in a pathway controlling immune cell trafficking during intestinal inflammation.","evidence":"Transcriptomic profiling of isolated human intestinal lymphatic endothelial cells and transwell transmigration assay","pmids":["31426584"],"confidence":"Medium","gaps":["Direct ligand (IL-19/IL-20/IL-24) responsible for transmigration effect not identified","Downstream signaling from IL-20RA in lymphatic endothelium not mapped","In vivo confirmation in animal models lacking"]},{"year":2021,"claim":"Convergent studies established that IL-20RA activates the JAK1-STAT3 axis in multiple contexts: in breast cancer it drives SOX2/PD-L1-mediated immune evasion, and miR-452 negatively regulates IL-20RA to suppress this pathway.","evidence":"Gain/loss-of-function experiments with in vivo tumor models (breast cancer); luciferase reporter assay validating miR-452 targeting of IL-20RA mRNA; CRISPR knockdown in rat GMH model confirming ERK/Nrf2 branch","pmids":["33456560","34283251","33532035"],"confidence":"Medium","gaps":["Whether JAK1-STAT3 and ERK/Nrf2 are activated simultaneously or context-dependently not resolved","Direct physical interaction between IL-20RA and JAK1 not demonstrated biochemically","Relative contribution of each ligand (IL-19/IL-20/IL-24) to STAT3 activation in tumors unknown"]},{"year":null,"claim":"Key unresolved questions include the full atomic structure of IL-20RA-containing ternary complexes, the mechanism of JAK1 recruitment to IL-20RA's intracellular domain, and whether IL-20RA signals through additional non-canonical pathways beyond JAK-STAT and ERK-Nrf2.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution ternary complex structure with full interface analysis published","JAK1 recruitment mechanism to IL-20RA intracellular domain unknown","Ligand-specific versus shared downstream signaling programs not systematically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,5]}],"complexes":["IL-20RA/IL-20R2","IL-22R1/IL-20R2"],"partners":["IL20RB","IL22RA1","IL20","IL19","IL24","JAK1","STAT3"],"other_free_text":[]},"mechanistic_narrative":"IL-20RA (IL-20R1) is a shared signaling subunit of heterodimeric type II cytokine receptor complexes that transduce signals from IL-19, IL-20, and IL-24 to regulate inflammation, tissue repair, and immune cell trafficking. IL-20RA pairs with IL-20R2 to bind IL-20 and IL-19, and IL-24 signals through both IL-20RA/IL-20R2 and IL-22R1/IL-20R2 heterodimers, activating STAT transcription factors, JAK1-STAT3, and ERK/Nrf2 pathways depending on cellular context [PMID:11706020, PMID:33532035, PMID:33456560]. Transcriptional control of IL-20RA itself is mediated by an NF-κB-bound enhancer element at the 6q23 locus, which contacts the IL-20RA promoter through chromatin looping [PMID:29483615]. In disease settings, IL-20RA signaling through JAK1-STAT3 drives liver fibrosis via TGF-β1 upregulation, promotes cancer stemness and immune evasion through SOX2 and PD-L1 induction, and regulates leukocyte transmigration across lymphatic endothelium in Crohn's disease [PMID:24763901, PMID:33456560, PMID:31426584]."},"prefetch_data":{"uniprot":{"accession":"Q9UHF4","full_name":"Interleukin-20 receptor subunit alpha","aliases":["Cytokine receptor class-II member 8","Cytokine receptor family 2 member 8","CRF2-8","IL-20R1","ZcytoR7"],"length_aa":553,"mass_kda":62.5,"function":"The IL20RA/IL20RB dimer is a receptor for IL19, IL20 and IL24. The IL20RA/IL10RB dimer is a receptor for IL26","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9UHF4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL20RA","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL20RA","total_profiled":1310},"omim":[{"mim_id":"606648","title":"INTERLEUKIN 22 RECEPTOR, ALPHA-2; IL22RA2","url":"https://www.omim.org/entry/606648"},{"mim_id":"605679","title":"INTERLEUKIN 26; IL26","url":"https://www.omim.org/entry/605679"},{"mim_id":"605621","title":"INTERLEUKIN 20 RECEPTOR, BETA; IL20RB","url":"https://www.omim.org/entry/605621"},{"mim_id":"605620","title":"INTERLEUKIN 20 RECEPTOR, ALPHA; IL20RA","url":"https://www.omim.org/entry/605620"},{"mim_id":"605619","title":"INTERLEUKIN 20; IL20","url":"https://www.omim.org/entry/605619"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"breast","ntpm":24.8},{"tissue":"skin 1","ntpm":35.5}],"url":"https://www.proteinatlas.org/search/IL20RA"},"hgnc":{"alias_symbol":["ZCYTOR7","IL-20R1"],"prev_symbol":[]},"alphafold":{"accession":"Q9UHF4","domains":[{"cath_id":"2.60.40.10","chopping":"34-130","consensus_level":"high","plddt":92.8612,"start":34,"end":130},{"cath_id":"2.60.40.10","chopping":"142-242","consensus_level":"high","plddt":93.5982,"start":142,"end":242},{"cath_id":"1.20.5","chopping":"254-279","consensus_level":"medium","plddt":89.6723,"start":254,"end":279}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHF4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHF4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHF4-F1-predicted_aligned_error_v6.png","plddt_mean":62.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL20RA","jax_strain_url":"https://www.jax.org/strain/search?query=IL20RA"},"sequence":{"accession":"Q9UHF4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHF4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHF4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHF4"}},"corpus_meta":[{"pmid":"11706020","id":"PMC_11706020","title":"Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11706020","citation_count":224,"is_preprint":false},{"pmid":"33456560","id":"PMC_33456560","title":"IL20RA signaling enhances stemness and promotes the formation of an immunosuppressive microenvironment in breast cancer.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33456560","citation_count":74,"is_preprint":false},{"pmid":"27799070","id":"PMC_27799070","title":"Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23.","date":"2016","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/27799070","citation_count":72,"is_preprint":false},{"pmid":"24763901","id":"PMC_24763901","title":"IL-20 and IL-20R1 antibodies protect against liver fibrosis.","date":"2014","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/24763901","citation_count":65,"is_preprint":false},{"pmid":"34336707","id":"PMC_34336707","title":"Super-Enhancer Induced IL-20RA Promotes Proliferation/Metastasis and Immune Evasion in Colorectal Cancer.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34336707","citation_count":34,"is_preprint":false},{"pmid":"29483615","id":"PMC_29483615","title":"CRISPR/cas9 mediated knockout of an intergenic variant rs6927172 identified IL-20RA as a new risk gene for multiple autoimmune diseases.","date":"2018","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/29483615","citation_count":23,"is_preprint":false},{"pmid":"18480827","id":"PMC_18480827","title":"Association analysis of IL20RA and IL20RB genes in psoriasis.","date":"2008","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/18480827","citation_count":22,"is_preprint":false},{"pmid":"34283251","id":"PMC_34283251","title":"MicroRNA 452 regulates IL20RA-mediated JAK1/STAT3 pathway in inflammatory colitis and colorectal cancer.","date":"2021","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/34283251","citation_count":21,"is_preprint":false},{"pmid":"31152679","id":"PMC_31152679","title":"Flexible regions govern promiscuous binding of IL-24 to receptors IL-20R1 and IL-22R1.","date":"2019","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/31152679","citation_count":19,"is_preprint":false},{"pmid":"31426584","id":"PMC_31426584","title":"mTOR-Dependent Stimulation of IL20RA Orchestrates Immune Cell Trafficking through Lymphatic Endothelium in Patients with Crohn's Disease.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31426584","citation_count":13,"is_preprint":false},{"pmid":"39154973","id":"PMC_39154973","title":"Fish IL-26 collaborates with IL-10R2 and IL-20R1 to enhance gut mucosal barrier during the antibacterial innate immunity.","date":"2024","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39154973","citation_count":9,"is_preprint":false},{"pmid":"36414129","id":"PMC_36414129","title":"Grass carp IL-20 binds to IL-20R2 but induces STAT3 phosphorylation via IL-20R1.","date":"2022","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36414129","citation_count":6,"is_preprint":false},{"pmid":"33532035","id":"PMC_33532035","title":"IL-20R Activation via rIL-19 Enhances Hematoma Resolution through the IL-20R1/ERK/Nrf2 Pathway in an Experimental GMH Rat Pup Model.","date":"2021","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/33532035","citation_count":6,"is_preprint":false},{"pmid":"39875436","id":"PMC_39875436","title":"Programmed cell death-related gene IL20RA facilitates tumor progression and remodels tumor microenvironment in thyroid cancer.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39875436","citation_count":4,"is_preprint":false},{"pmid":"23811545","id":"PMC_23811545","title":"Detection of IL-20R1 and IL-20R2 mRNA in C57BL/6 mice astroglial cells and brain cortex following LPS stimulation.","date":"2013","source":"Iranian journal of immunology : IJI","url":"https://pubmed.ncbi.nlm.nih.gov/23811545","citation_count":4,"is_preprint":false},{"pmid":"39712242","id":"PMC_39712242","title":"IL-20RA is Associated with the Risk of Diabetic Microangiopathy: A Bidirectional Mendelian Randomization Analysis and Clinical Validation.","date":"2024","source":"Diabetes, metabolic syndrome and obesity : targets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39712242","citation_count":2,"is_preprint":false},{"pmid":"40185911","id":"PMC_40185911","title":"The signature based on interleukin family and receptors identified IL19 and IL20RA in promoting nephroblastoma progression through STAT3 pathway.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40185911","citation_count":1,"is_preprint":false},{"pmid":"22232181","id":"PMC_22232181","title":"Purification, crystallization and preliminary X-ray diffraction analysis of the IL-20-IL-20R1-IL-20R2 complex.","date":"2011","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/22232181","citation_count":0,"is_preprint":false},{"pmid":"39765872","id":"PMC_39765872","title":"IL20RA Is the Key Factor Contributing to the Stronger Antioxidant Capacity of Rongchang Pig Sertoli Cells.","date":"2024","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39765872","citation_count":0,"is_preprint":false},{"pmid":"40989758","id":"PMC_40989758","title":"Downregulation of IL-20RA in Cerebrospinal Fluid Associated with the Risk of Moyamoya Disease: A Molecular Signatures Analysis with an Inflammation Proteomics Landscape.","date":"2025","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/40989758","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.22.24315951","title":"Genetically Predicted Inflammatory Proteins Mediate the Association Between Gut Microbiota and Preterm Delivery: A Mendelian Randomization Study","date":"2024-10-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.22.24315951","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12329,"output_tokens":2618,"usd":0.038129},"stage2":{"model":"claude-opus-4-6","input_tokens":5969,"output_tokens":2257,"usd":0.129405},"total_usd":0.167534,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"IL-24 (MDA-7/MOB-5) signals through two heterodimeric receptors: IL-22R1/IL-20R2 and IL-20R1/IL-20R2 (where IL-20R1 = IL-20RA). COS cells transfected with either receptor heterodimer bind IL-24 with similar saturation kinetics, and IL-24 binding to these receptors activates STAT transcription factors in keratinocytes and baby hamster kidney cells.\",\n      \"method\": \"Ligand-receptor binding assay, STAT activation assay in COS cells and keratinocytes, transfection of ectopic receptors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding and signaling assays with multiple cell types, replicated in endogenous and ectopic systems\",\n      \"pmids\": [\"11706020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The IL-20-IL-20R1(IL-20RA)-IL-20R2 ternary complex was crystallized, with crystals diffracting to 3 Å resolution, establishing that IL-20RA forms a ternary complex with IL-20 and IL-20R2.\",\n      \"method\": \"Protein purification, crystallization, X-ray diffraction\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology and crystallization communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure obtained but preliminary report without full structure determination or functional mutagenesis\",\n      \"pmids\": [\"22232181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-20 signals through IL-20R1 (IL-20RA)-containing receptor complexes on hepatic stellate cells and hepatocytes to upregulate TGF-β1, TNF-α, and Col-I; anti-IL-20R1 monoclonal antibody (51D) and IL-20R1-deficient mice were protected from CCl4-induced liver fibrosis, placing IL-20RA upstream of TGF-β1 signaling in liver injury.\",\n      \"method\": \"Anti-IL-20R1 monoclonal antibody blockade, IL-20R1 knockout mice, CCl4-induced liver injury model, cell-based assays\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout plus antibody blockade with defined fibrosis phenotype, multiple orthogonal approaches\",\n      \"pmids\": [\"24763901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Flexible regions of IL-24 govern its promiscuous binding to IL-20R1 (IL-20RA) and IL-22R1 (shared receptors 1); a single wild-type residue T198 on IL-24 is critical for binding affinity to IL-20R1 and IL-22R1, as its mutation abolishes binding while reintroduction restores ~80% binding affinity and signaling capacity.\",\n      \"method\": \"Protein engineering, binding affinity measurements, signaling assays, homology modeling, crystallography (IL-24B, PDB ID 6GG1)\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure combined with site-specific mutagenesis and functional signaling assays\",\n      \"pmids\": [\"31152679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Crohn's disease intestinal lymphatic endothelial cells, mTOR signaling drives IL-20RA expression, and IL-20RA-mediated intracellular signaling controls leukocyte (LPMC) transmigration through the lymphatic endothelium, placing IL-20RA downstream of mTOR in regulating immune cell trafficking.\",\n      \"method\": \"Transcriptomic profiling of isolated human intestinal lymphatic endothelial cells, transwell co-culture transmigration assay with LPMCs\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional transmigration assay with transcriptomic pathway identification, single lab\",\n      \"pmids\": [\"31426584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-20RA activates the JAK1-STAT3-SOX2 signaling axis in breast cancer cells, leading to increased expression of PD-L1 and reduced recruitment of CD8+ T cells and NK cells; IL-20RA also increases the proportion of myeloid-derived suppressor cells, promoting an immunosuppressive tumor microenvironment.\",\n      \"method\": \"Gain- and loss-of-function experiments, western blot, flow cytometry, in vivo mouse tumor models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD/OE, flow cytometry, in vivo), single lab\",\n      \"pmids\": [\"33456560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MiR-452 directly targets IL-20RA mRNA (validated by luciferase reporter assay); overexpression of MiR-452 or IL-20RA knockdown decreases expression of IL-20RA, JAK1, and STAT3 (but not STAT1), establishing that IL-20RA mediates JAK1-STAT3 signaling downstream of miR-452 regulation.\",\n      \"method\": \"Luciferase reporter assay, siRNA knockdown, western blot, RT-PCR\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target validation by luciferase assay combined with KD phenotype, single lab\",\n      \"pmids\": [\"34283251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-19 signals through IL-20R1 (IL-20RA) to activate ERK and Nrf2, promoting CD163 expression and hematoma clearance after germinal matrix hemorrhage; IL-20R1 CRISPR knockdown abolished the beneficial effects of rIL-19 treatment.\",\n      \"method\": \"CRISPR knockdown of IL-20R1 in rat pup GMH model, western blot, immunohistochemistry, hemoglobin assay, neurobehavioral testing\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR loss-of-function with defined molecular pathway (IL-20R1/ERK/Nrf2) and functional readout\",\n      \"pmids\": [\"33532035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The intergenic variant rs6927172 at 6q23 acts as a regulatory element that controls IL-20RA expression through chromatin looping; CRISPR/Cas9 deletion of this element altered IL-20RA (and TNFAIP3) expression, with EMSA showing the variant affects NF-κB transcription factor binding at this locus.\",\n      \"method\": \"CRISPR/Cas9 deletion, EMSA, western blot, chromatin conformation capture (3C), TALE-based transcriptional analysis\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (CRISPR KO, EMSA, 3C, TALE) establishing regulatory mechanism\",\n      \"pmids\": [\"29483615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-20RA promotes epithelial-mesenchymal transition (EMT) through the STAT3/SNAIL pathway in Wilms tumor; IL-20RA knockdown decreased EMT markers, and IL-20RA was shown to act upstream of STAT3-SNAIL in driving tumor progression.\",\n      \"method\": \"siRNA knockdown, western blot, functional assays for EMT\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single KD approach with pathway inference\",\n      \"pmids\": [\"40185911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In pig Sertoli cells, IL-20RA knockdown affected mitochondrial superoxide production and catalase secretion, indicating IL-20RA mediates antioxidant protection of mitochondria in these cells.\",\n      \"method\": \"siRNA knockdown, ROS measurement, mitochondrial function assays, transcriptomic analysis\",\n      \"journal\": \"Antioxidants (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single KD experiment in a non-mammalian model (pig), single lab\",\n      \"pmids\": [\"39765872\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-20RA (IL-20R1) functions as the signaling subunit of heterodimeric cytokine receptor complexes (IL-20RA/IL-20R2 and IL-22R1/IL-20R2) that bind IL-20, IL-19, and IL-24; upon ligand binding, IL-20RA activates intracellular JAK1-STAT3 (and ERK/Nrf2) signaling cascades to regulate inflammation, tissue homeostasis, immune cell trafficking, and—when dysregulated—cancer stemness and immune evasion, with receptor expression itself controlled by an NF-κB-bound enhancer element at 6q23.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-20RA (IL-20R1) is a shared signaling subunit of heterodimeric type II cytokine receptor complexes that transduce signals from IL-19, IL-20, and IL-24 to regulate inflammation, tissue repair, and immune cell trafficking. IL-20RA pairs with IL-20R2 to bind IL-20 and IL-19, and IL-24 signals through both IL-20RA/IL-20R2 and IL-22R1/IL-20R2 heterodimers, activating STAT transcription factors, JAK1-STAT3, and ERK/Nrf2 pathways depending on cellular context [PMID:11706020, PMID:33532035, PMID:33456560]. Transcriptional control of IL-20RA itself is mediated by an NF-κB-bound enhancer element at the 6q23 locus, which contacts the IL-20RA promoter through chromatin looping [PMID:29483615]. In disease settings, IL-20RA signaling through JAK1-STAT3 drives liver fibrosis via TGF-β1 upregulation, promotes cancer stemness and immune evasion through SOX2 and PD-L1 induction, and regulates leukocyte transmigration across lymphatic endothelium in Crohn's disease [PMID:24763901, PMID:33456560, PMID:31426584].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that IL-20RA functions as a ligand-binding subunit in two heterodimeric receptor complexes for IL-24 resolved how a single cytokine engages distinct receptor pairs to activate STAT signaling.\",\n      \"evidence\": \"Ligand-receptor binding and STAT activation assays in COS cells, keratinocytes, and BHK cells transfected with IL-20R1/IL-20R2 or IL-22R1/IL-20R2\",\n      \"pmids\": [\"11706020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream STAT family member specificity not resolved\", \"Binding affinities for IL-19 and IL-20 through these complexes not measured\", \"No structural basis for receptor assembly\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Crystallization of the IL-20–IL-20RA–IL-20R2 ternary complex provided the first structural evidence that IL-20RA directly contacts both ligand and co-receptor in a defined stoichiometric assembly.\",\n      \"evidence\": \"Protein purification and X-ray crystallography at 3 Å resolution\",\n      \"pmids\": [\"22232181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full atomic structure and interface residue analysis not yet reported\", \"No mutagenesis validation of predicted contact sites\", \"Structure of IL-19 or IL-24 ternary complexes not determined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that IL-20RA-deficient mice and anti-IL-20RA antibody blockade prevented liver fibrosis established IL-20RA as a required upstream activator of TGF-β1 and pro-fibrotic gene expression in hepatic stellate cells.\",\n      \"evidence\": \"IL-20R1 knockout mice and anti-IL-20R1 monoclonal antibody (51D) in CCl4-induced liver fibrosis model\",\n      \"pmids\": [\"24763901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise signaling intermediates between IL-20RA and TGF-β1 induction not mapped\", \"Whether IL-19 or IL-24 also drives fibrosis through this receptor not tested\", \"Human disease relevance not validated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of an NF-κB-bound intergenic enhancer at 6q23 that controls IL-20RA expression via chromatin looping revealed how genetic variation at this locus can tune receptor abundance.\",\n      \"evidence\": \"CRISPR/Cas9 enhancer deletion, EMSA, chromatin conformation capture (3C), and TALE-based transcriptional analysis\",\n      \"pmids\": [\"29483615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type specificity of enhancer activity not fully characterized\", \"Quantitative relationship between enhancer variant genotype and surface IL-20RA protein levels not established\", \"Whether this enhancer co-regulates TNFAIP3 independently of IL-20RA not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Structural and mutagenesis studies on IL-24 identified T198 as a critical residue governing promiscuous binding to IL-20RA and IL-22R1, explaining how flexible ligand regions enable receptor sharing.\",\n      \"evidence\": \"Protein engineering, binding affinity measurements, signaling assays, and crystal structure of IL-24B variant (PDB 6GG1)\",\n      \"pmids\": [\"31152679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reciprocal mutations on IL-20RA that affect binding not identified\", \"Whether IL-19 uses analogous structural determinants unknown\", \"No kinetic (SPR) data for mutant binding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Finding that mTOR signaling drives IL-20RA expression in Crohn's disease lymphatic endothelial cells and that IL-20RA mediates leukocyte transmigration placed the receptor in a pathway controlling immune cell trafficking during intestinal inflammation.\",\n      \"evidence\": \"Transcriptomic profiling of isolated human intestinal lymphatic endothelial cells and transwell transmigration assay\",\n      \"pmids\": [\"31426584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ligand (IL-19/IL-20/IL-24) responsible for transmigration effect not identified\", \"Downstream signaling from IL-20RA in lymphatic endothelium not mapped\", \"In vivo confirmation in animal models lacking\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Convergent studies established that IL-20RA activates the JAK1-STAT3 axis in multiple contexts: in breast cancer it drives SOX2/PD-L1-mediated immune evasion, and miR-452 negatively regulates IL-20RA to suppress this pathway.\",\n      \"evidence\": \"Gain/loss-of-function experiments with in vivo tumor models (breast cancer); luciferase reporter assay validating miR-452 targeting of IL-20RA mRNA; CRISPR knockdown in rat GMH model confirming ERK/Nrf2 branch\",\n      \"pmids\": [\"33456560\", \"34283251\", \"33532035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JAK1-STAT3 and ERK/Nrf2 are activated simultaneously or context-dependently not resolved\", \"Direct physical interaction between IL-20RA and JAK1 not demonstrated biochemically\", \"Relative contribution of each ligand (IL-19/IL-20/IL-24) to STAT3 activation in tumors unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full atomic structure of IL-20RA-containing ternary complexes, the mechanism of JAK1 recruitment to IL-20RA's intracellular domain, and whether IL-20RA signals through additional non-canonical pathways beyond JAK-STAT and ERK-Nrf2.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution ternary complex structure with full interface analysis published\", \"JAK1 recruitment mechanism to IL-20RA intracellular domain unknown\", \"Ligand-specific versus shared downstream signaling programs not systematically dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\n      \"IL-20RA/IL-20R2\",\n      \"IL-22R1/IL-20R2\"\n    ],\n    \"partners\": [\n      \"IL20RB\",\n      \"IL22RA1\",\n      \"IL20\",\n      \"IL19\",\n      \"IL24\",\n      \"JAK1\",\n      \"STAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}